This invention relates to liquid polymeric compositions, or occludant precursors, that may be injected via a catheter to form occlusions in a selected body region. In particular, the compositions may be used to block blood flow in malfunctioning human organs such as the kidney, spleen, and liver, or to block blood flow into the malfunctioning areas of blood vessels such as arterio-venous malformations (AVM) and aneurysms.
The artificial blocking of blood flow is known generically as "embolization." The embolization of a vessel in an organ may be used to treat a variety of maladies; typically, though, embolization is used: 1) to control the bleeding caused by trauma, 2) to prevent profuse blood loss during an operation requiring dissection of bloodvessels, 3) to obliterate a portion of or a whole organ having a tumor, or 4) to block the blood flow into abnormal blood vessel structures such as AVM's and aneurysms.
There are a variety of materials and devices which have been used for embolization. These include platinum and stainless steel microcoils, polyvinyl alcohol sponges (Ivalone), and cyanoacrylate glues (n-butyl and iso-butyl cyanoacrylate glue). See, Interventional Radiology, Dandlinger et al, ed., Thieme, N.Y., 1990:295-313. Of these, the cyanoacrylate glues have an advantage over other embolic materials in ease of delivery in that they are the only liquid embolics currently available to neurosurgeons. However, the constituent cyanoacrylate polymers have the disadvantage of being biodegradable. The degradation product, formaldehyde, is highly toxic to the neighboring tissues. See, Vinters et al, "The histotoxocity of cyanoacrylate: a selective review", Neuroradiology 1985; 27:279-291. Another disadvantage of cyanoacrylate materials is that the polymer will adhere both to the blood vessel and to the tip of the catheter. Thus physicians must retract the catheter immediately after injection of the cyanoacrylate embolic material or risk adhesion of the cyanoacrylate and the catheter to the vessel.
Another class of liquid embolic materials--precipitative materials--was invented in late 80's. See, Sugawara et al, "Experimental investigations concerning a new liquid embolization method: Combined administration of ethanol-estrogen and polyvinyl acetate", Neuro Med Chir (Tokyo) 1993; 33:71-76; Taki et al, "A new liquid material for embolization of arterio-venous malformations", AJNR 1990:11:163-168; Mandai et al, "Direct Thrombosis of aneurysms with cellulose acetate polymer. Part I: Results of thrombosis in experimental aneurysms." J. Neurosurgery 1992; 77:497-500. These materials employ a different mechanism in forming synthetic emboli than do the cyanoacrylate glues. Cyanoacrylate glues are monomeric and rapidly polymerize upon contact with blood. Precipitative materials, on the other hand, are pre-polymerized chains that precipitate into an aggregate upon contact with blood.
In the precipitation method, the polymer is dissolved in a solvent that is miscible with blood, and upon contact with that blood, the solvent is diluted and the water-insoluble polymer precipitates. Ideally, the precipitate forms a solid mass and thus occludes the vessel.
The first such precipitative material used in this way was polyvinyl acetate (PVAc). Takahashi et al. dissolved the polymer in an ethanol/water mixture and delivered the mixture to an AVM for embolization. Also, poly(ethylene-co-vinyl alcohol) ("EVAL") and cellulose acetate (CA) dissolved in 100% DMSO have also been used in clinical procedures. See, Taki et al, "A new liquid material for embolization of arterovenous malformations", AJNR 1990; 11:163-168 and Mandai et al, "Direct thrombosis of aneurysms with cellulose polymer: Part I: Results of thrombosis in experimental aneurysms", J. Neurosurgery 1992; 77:497-500.
One potential problem in using the precipitating polymers mentioned above is the use of organic solvents to dissolve the polymers, i.e., ethanol for PVAc and DMSO for EVAL and CA. These materials are strong organic solvents that can dissolve the catheter hub, and, in the case of DMSO, can damage microcapillary vessels and surrounding tissues. These solvents are also known to cause vasospasm of blood vessels. Although PVAc is soluble in solvents which are milder than those needed for dissolution of EVAL or CA, a PVAc solution has a problem of its own: its radio-opacity is very low, i.e., the contrast concentration is only 100 mg I/ml equivalent.
None of the cited references utilize the solvents and precipitating polymer described herein nor do they use milder organic solvents that are still insoluble in blood. The prior art compositions are not suitable for dissolving high levels of contrast medium.